1. Field of the Invention
The present invention relates to transdermal therapeutic systems, self-adhesive flat bandages, in particular cosmetic and medicinal plasters, containing 4-n-butylresorcinol.
2. Discussion of Background Information
Melanocytes are responsible for the pigmenting of the skin; these are found in the lowest layer of the epidermis, the Stratum basale, alongside the basal cells as pigment-forming cells which, depending on the skin type, occur either individually or in clusters of varying size.
Melanocytes contain, as characteristic cell organelles, melanosomes, in which the melanin is formed. Inter alia, upon stimulation by UV radiation, melanin is formed to a greater extent. It is transported via the living layers of the epidermis (keratinocytes) ultimately into the horny layer (corneocytes) and brings about a more or less pronounced brownish to brown-black skin color.
Melanin is formed as the end stage of an oxidative process in which tyrosine is converted, under the co-action of the enzyme tyrosinase, via several intermediates, to the brown to brown-black eumelanins (DHICA and DHI melanin), or, with the participation of sulfur-containing compounds, to the reddish pheomelanin. DHICA and DHI melanin are formed via the common intermediates dopaquinone and dopachrome. The latter, sometimes with the participation of further enzymes, is converted either to indole-5,6-quinonecarboxylic acid or into indole-5,6-quinone, from which the two specified eumelanins are formed.
The formation of pheomelanin proceeds inter alia via the intermediates dopaquinone and cysteinyldopa. The expression of the melanin-synthesizing enzymes is controlled by a specific transcription factor (microphthalmia-associated transcription factor, MITF). Besides the described enzymatic processes of the melanin synthesis, further proteins are also of importance for the melanogenesis in the melanosomes. An important role here appears to be attributed to the so-called p-protein, although the exact function is still unclear.
As well as the above-described process of the melanin synthesis in the melanocytes, the transfer of the melanosomes, their stay in the epidermis and also their degradation and the degradation of the melanin are also of decisive importance for the pigmenting of the skin. It was shown that the PAR-2 receptor is important for the transport of the melanosomes from the melanocytes into the keratinocytes (M. Seiberg et al., 2000, J. Cell. Sci., 113:3093-101).
In addition, the size and shape of the melanosomes have an influence on their light-scattering properties and thus the color appearance of the skin. For example, in black Africans there are more large spheroidal individual melanosomes whereas in Caucasians, smaller melanosomes occurring in groups are to be found.
Problems with hyperpigmentation of the skin have a wide variety of causes and/or are accompanying phenomena of many biological processes, e.g. UV radiation (e.g. freckles, Ephelides), genetic disposition, incorrect pigmentation of the skin during wound healing or scarring (post-inflammatory hyperpigmentation) or skin aging (e.g. Lentigines seniles).
After inflammatory reactions, the pigmentation system of the skin reacts with sometimes opposite reactions. This can lead either to post-inflammatory hyperpigmentations or hypopigmentations. Post-inflammatory hypomelanoses often arise inter alia in conjunction with atopy, Lupus erythematosus and psoriasis. The different reaction forms of the pigmentation system of human skin as a result of inflammatory phenomena are understood only very incompletely.
Problems with post-inflammatory hyperpigmentation often occur in darker skin types. Particularly in colored males, the problem of Pseudofollikulitis barbae is known, which is associated with cosmetically undesired incorrect pigmentation and/or leads to this. Forms of melasma, which occur in particular in women of Asiatic origin on the face and on the décolletage area, and also various forms of irregular pigmentation of the skin are also types of post-inflammatory hyperpigmentations. In addition, dark circles around the eyes are also considered to be a form of post-inflammatory hyperpigmentations, the underlying inflammation in most cases proceeding without clinical manifestations.
In many cases, post-inflammatory incorrect pigmentation of this type is increased further by the action of sunlight (UV light) without resulting in a UV-induced inflammation (sunburn).
Active ingredients and preparations are known which counteract skin pigmentation. In practical use are essentially preparations based on hydroquinone, although, on the one hand, these only exhibit their effect after application for several weeks, and, on the other hand, their excessively long application is unacceptable for toxicological reasons. Albert Kligman et al. has developed a so-called triformula which constitutes a combination of 0.1% tretinoin, 5.0% hydroquinone, 0.1% dexamethasone (A. Kligman, 1975, Arch. Dermatol., 111:40-48). However, this formulation too is highly disputed on account of possible irreversible changes in the pigmentation system of the skin.
In addition, skin-peeling methods (chemical and mechanical peels) are used, although these often lead to inflammatory reactions and, on account of post-inflammatory hyperpigmentations which may subsequently arise, can even lead to greater pigmentation instead of reduced pigmentation. All of these customary methods, which are also used for treating post-inflammatory hyperpigmentations, are characterized by distinct side effects.
Cosmetic preparations with 4-n-butylresorcinol are known, for example from EP 1 490 017.
4-n-Butylresorcinol, CAS[18979-61-8], is characterized by the chemical structure

4-n-Butylresorcinol is also called rucinol or lucinol. It inhibits the production of melanin by inhibiting the enzyme tyrosinase required for the synthesis of melanin (melanogenesis). The production of melanin is firstly inhibited, then the production of black melanin, which is responsible for the intense coloration of pigment spots, is blocked.
4-n-Butylresorcinol has the formulatory disadvantage that it has a tendency to discolor—and to discolor cosmetic or dermatological preparations comprising it.
Transdermal therapeutic systems (“TTS”) are known per se. A disadvantage of TTS is that usually only ca. 10% to 20% of the active ingredient content of the plaster are released during the application time. (Kommentar zum Europäischen Arzneibuch [Commentary on the European pharmacopeia], Wissenschaftliche Verlagsgesellschaft Stuttgart, status: update 2009).
It was therefore the object of the invention below to provide remedies for the disadvantages of the prior art.